Sirolimus-induced Pneumonitis Complicated by Pentamidine-induced Phospholipidosis in a Renal Transplant Recipient: A Case Report

Filippone, Edward J.; Carson, JP; Beckford, Rosemarie; Jaffe, B.C.; Newman, Eric D.; Awsare, Bharat; Doria, Cataldo; Farber, John L.

doi:10.1016/j.transproceed.2011.06.060

Cited by 20 publications

(9 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consideration of rapamycin's complex actions, we and others suggest it should be handled carefully for clinical uses. [14][15][16]30,31 In addition, we also show here the hypothesis that monotherapy with rapamycin may be unhelpful but combined inhibition of mTOR and PI3K may be more effective therapeutic strategy for lung fibrosis. CCN2 is a multifunctional, matricellular protein that is widely documented to relate to the progression of various fibroproliferative diseases and patients outcome.…”

Section: Discussionsupporting

confidence: 61%

“…30,31 In this study, we showed that lung fibroblast would respond to rapamycin by augmenting CCN2 expression via PI3K-AKT pathway. In fact, in tumor treatment, it was said that there were limitations of monotherapy for inhibiting feedbackregulated pathways and suggested that combined treatment with mTOR and P3IK/MAPK inhibitors would show more anti-tumor activity in a wide range of human malignance.…”

Section: Resultsmentioning

confidence: 69%

See 1 more Smart Citation

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Dai

Geng

et al. 2015

Laboratory Investigation

View full text Add to dashboard Cite

Excessive production of connective tissue growth factor (CTGF, CCN2) and increased motor ability of the activated fibroblast phenotype contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, molecules and signal pathways regulating CCN2 expression and migration of lung fibroblasts are still elusive. We hypothesize that rapamycin, via binding and blocking mammalian target of rapamycin (mTOR) complex (mTORC), affects CCN2 expression and migration of lung fibroblasts in vitro. Primary normal and fibrotic human lung fibroblasts were isolated from lung tissues of three patients with primary spontaneous pneumothorax and three with IPF. Cells were incubated with regular medium, or medium containing rapamycin, human recombinant transforming growth factor (TGF)-β1, or both. CCN2 and tissue inhibitor of metalloproteinase (TIMP)-1 expression in cells or supernatant was detected. Wound healing and migration assay was used to measure the migratory potential. TGF-β type I receptor (TβRI)/Smad inhibitor, SB431542 and phosphoinositide 3-kinase (PI3K) inhibitor, LY294002 were used to determine rapamycin's mechanism of action. We demonstrated that rapamycin amplified basal or TGF-β1-induced CCN2 mRNA and protein expression in normal or fibrotic fibroblasts by Smad-independent but PI3K-dependent pathway. Additionally, rapamycin also enhanced TIMP-1 expression as indicated by ELISA. However, wound healing and migrating assay showed rapamycin did not affect the mobility of fibroblasts. Collectively, this study implies a significant fibrogenic induction activity of rapamycin by activating AKT and inducing CCN2 expression in vitro and provides the possible mechanisms for the in vivo findings which previously showed no antifibrotic effect of rapamycin on lung fibrosis.

show abstract

Section: Discussionsupporting

confidence: 61%

Section: Resultsmentioning

confidence: 69%

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Dai

Geng

et al. 2015

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…However, whether rapamycin can be used safety in human aging due to the side effect profile of rapamycin treatment is a major question. For example, rapamycin has been associated with the development of lung toxicity in patients, which can be treated clinically (55). …”

Section: Discussionmentioning

confidence: 99%

Short-Term Treatment With Rapamycin and Dietary Restriction Have Overlapping and Distinctive Effects in Young Mice

Fok¹,

Zhang²,

Salmon

et al. 2012

The Journals of Gerontology: Series A

View full text Add to dashboard Cite

Because rapamycin, an inhibitor of the nutrient sensor mammalian target of rapamycin, and dietary restriction both increase life span of mice, it has been hypothesized that they act through similar mechanisms. To test this hypothesis, we compared various biological parameters in dietary restriction mice (40% food restriction) and mice fed rapamycin (14 ppm). Both treatments led to a significant reduction in mammalian target of rapamycin signaling and a corresponding increase in autophagy. However, we observed striking differences in fat mass, insulin sensitivity, and expression of cell cycle and sirtuin genes in mice fed rapamycin compared with dietary restriction. Thus, although both treatments lead to significant downregulation of mammalian target of rapamycin signaling, these two manipulations have quite different effects on other physiological functions suggesting that they might increase life span through a common pathway as well as pathways that are altered differently by dietary restriction and rapamycin.

show abstract

“…The results of CT scans and lung biopsy suggested a synergistic effect of both drugs on pulmonary toxicity (30). Our patient was never treated with mTORi, and the postmortem picture of the lung tissue in our case did not demonstrate any pathology related to pentamidine toxicity (presence of vacuoles in type 2 pneumocytes and macrophages) (30). Another important part of the treatment protocol in our case was PF (overall 18 procedures).…”

Section: E116mentioning

confidence: 54%

Fatal rituximab‐associated lung injury syndrome in a patient treated with rituximab for recurrence of post‐transplant nephrotic syndrome

Grenda

Jarmużek

Rubik

et al. 2015

Pediatric Transplantation

View full text Add to dashboard Cite

A 10-yr-old patient with end-stage renal failure due to multidrug-resistant NS was transplanted with renal graft from deceased donor and presented immediate recurrence of NS. PF was started on day 3 and patient received MP pulses, however with no effect. Rituximab (4 × 375 mg/m(2)) was administered. Chest radiographs taken at that time were normal. Partial remission was achieved and the patient was discharged in good condition. Sequential recurrence appeared two wk afterward. Twelve sessions of PF were performed and six pulses of MP were given, effecting a partial remission. Three months after the last dose of rituximab, patient was admitted with increasing respiratory failure, requiring mechanical ventilation. Infectious background, including CMV, BKV, mycoplasma, and pneumocystis, was not confirmed. The patient was treated with MP pulses, IVIG, and a variety of antibiotics. Ground-glass opacity was confirmed on lung CT images. Respiratory failure worsened, despite aggressive ventilation and patient passed away after three wk at ICU. A destruction of alveolar epithelium and extended pulmonary fibrosis was confirmed in the autopsy report. The case represents a fatal RALI.

show abstract

Sirolimus-induced Pneumonitis Complicated by Pentamidine-induced Phospholipidosis in a Renal Transplant Recipient: A Case Report

Cited by 20 publications

References 21 publications

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Short-Term Treatment With Rapamycin and Dietary Restriction Have Overlapping and Distinctive Effects in Young Mice

Fatal rituximab‐associated lung injury syndrome in a patient treated with rituximab for recurrence of post‐transplant nephrotic syndrome

Contact Info

Product

Resources

About